ClinVar Miner

Submissions for variant NM_001368894.2(PAX6):c.664C>T (p.Arg222Trp)

dbSNP: rs757259413
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413794 SCV000490693 pathogenic not provided 2022-08-08 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016)
Eurofins Ntd Llc (ga) RCV000413794 SCV000708115 likely pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000984424 SCV001430017 pathogenic Aniridia 1 2020-07-21 criteria provided, single submitter clinical testing
Invitae RCV001388984 SCV001590181 pathogenic Aniridia 1; Irido-corneo-trabecular dysgenesis 2022-02-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372441). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757259413, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV002463362 SCV002757803 pathogenic Foveal hypoplasia 1; Irido-corneo-trabecular dysgenesis 2022-12-01 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004529567 SCV004107619 pathogenic PAX6-related disorder 2023-06-01 criteria provided, single submitter clinical testing The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic.
Wessex Regional Genetics Laboratory, Salisbury District Hospital RCV000984424 SCV001055779 likely pathogenic Aniridia 1 2019-08-15 no assertion criteria provided clinical testing

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